The objectives of the proposed research are: 1. to improve our understanding of the actions of narcotic analgesics and narcotic antagonists in man, 2. to provide a sound basis for the clinical applications of these drugs, especially during anesthesia when very large doses of morphine and its surrogates are administered to man, and 3. to determine the responses of alcoholic and drug dependent patients to anesthetic drugs. The experimental approach to these objectives involves correlation of plasma and central nervous system concentrations of selected narcotic analgesics with their pharmacological effects in human and animal subjects. Sensitive and specific methods of analysis of narcotic analgesics in biological specimens involve solvent extraction procedures in conjunction with gas chromatography, mass spectrometry, spectrophotofluorometry, radioimmunoassay and other radioisotopic techniques. The anesthetic setting with extensive monitoring of physiological and biochemical functions facilitates correlation of the biological disposition of the narcotic analgesics with their pharmacological effects (e.g., suppression of responses to noxious stimuli, ventilatory depression). In addition to improving patient care, this pharmacokinetic study will contribute basic quantitative information concerning the actions of narcotic analgesics and their antagonists in man. Adequate correlations of biological effects with the disposition of these drugs in vivo will enable us 1. to define dosage regimens and drugs of choice for optimal use of the narcotic analgesics in man, 2. to assess the development and degree of tolerance, 3. to investigate the basis of interactions of narcotic analgesics with other drugs, and 4. to recommend modifications of dosage regimens in various disease states (e.g., drug and alcohol abuse, liver failure).